Vinyl Esters Research Articles

Chemoenzymatic synthesis of symmetrically structured triacylglycerols possessing short-chain fatty acids

Synthesis of symmetrically structured triacylglycerols possessing bioactive n−3 polyunsaturated fatty acids (eicosapentaenoic acid or docosahexaenoic acid) at the 2-position and a short-chain fatty acid (C 2, C 4, C 6) located at the end-positions by a highly efficient two-step chemoenzymatic process is described. Full regiocontrol devoid of any acyl-migration side reactions was obtained in both a lipase promoted step to introduce the short-chain fatty acids exclusively into the primary alcohol positions of glycerol using activated vinyl esters at low temperature and a subsequent coupling reaction involving free EPA and DHA using EDAC as a coupling agent.

Regioselective Lipase-Catalyzed Synthesis of 3-O-Acyl Derivatives of Resveratrol and Study of Their Antioxidant Properties

One of the approaches to increasing the bioavailability of resveratrol is to protect its 3-OH phenolic group. In this work, regioselective acylation of resveratrol at 3-OH was achieved by transesterification with vinyl acetate catalyzed by immobilized lipase from Alcaligenes sp. (lipase QLG). The maximum yield of 3-O-acetylresveratrol was approximately 75%, as the lipase also catalyzes its further acetylation affording the diester 3,4'-di-O-acetylresveratrol and finally the peracetylated derivative. Long saturated and unsaturated fatty acid vinyl esters were also effective as acyl donors with similar regioselectivity. In contrast, lipase B from Candida antarctica catalyzes the acylation of the phenolic group 4'-OH with 80% yield and negligible formation of higher esters. The analysis of the antioxidant properties showed that the Trolox equivalent antioxidant capability (TEAC) values for the acetyl and stearoyl derivatives at 3-OH were, respectively, 40% and 25% referred to resveratrol. The addition of an acyl chain in the 3-OH position caused a higher loss of activity compared with that at the 4'-OH.

Vinyl esters: Low cytotoxicity monomers for the fabrication of biocompatible 3D scaffolds by lithography based additive manufacturing

AbstractLithography based additive manufacturing technologies (AMT) like stereolithography or digital light processing have become appealing methods for the fabrication of 3D cellular scaffolds for tissue engineering and regenerative medicine. To circumvent the use of (meth)acrylate‐based photopolymers, that suffer from skin irritation and sometimes cytotoxicity, new monomers based on vinyl esters were prepared. In vitro cytotoxicity studies with osteoblast‐like cells proofed that monomers based on vinyl esters are significantly less cytotoxic than (meth)acrylates. Photoreactivity was followed by photo‐differential scanning calorimetry and the mechanical properties of the photocured materials were screened by nanoindentation. Conversion rates and indentation moduli between those of acrylate and methacrylate references could be observed. Furthermore, osteoblast‐like cells were successfully seeded onto polymer specimens. Finally, we were able to print a 3D test structure out of a vinyl ester‐based formulation by μ‐SLA with a layer thickness of 50 μm. For in vivo testing of vinyl esters these 3D scaffolds were implanted into surgical defects of the distal femoral bone of adult New Zealand white rabbits. The obtained histological results approved the excellent biocompatibility of vinyl esters. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2009

Highly selective transport of transesterification reaction compounds through supported liquid membranes containing ionic liquids based on the tetrafluoroborate anion

We previously reported the selective simultaneous separation of the substrates and products of a transesterification reaction (vinyl butyrate, 1-butanol, butyl butyrate and butyric acid) through supported liquid membranes (SLMs) based on 1-n-alkyl-3-methylimidazolium cations combined with tetrafluoroborate, hexafluorophosphate and bis{(trifluoromethyl)sulfonyl}imide anions. The best results were obtained by the use of tetrafluoroborate based ionic liquids, which led us to further investigate the use of these new supported liquid membranes for the selective separation of different substrates and products of transesterification reactions. With this aim, the permeability of sixteen different organic compounds (vinyl esters, aliphatic esters, alcohols and carboxylic acids) through SLMs containing tetrafluoroborate based ionic liquids ([bmim+][BF4−] and [omim+][BF4−]) were evaluated. It was found that permeability increased as the alkyl chain length decreased for the same organic functional group. In addition, significant permeability differences were found between the different organic functional groups.As regards the operational stability of these SLMs, they were seen to be very stable when tested over eight continuous cycles of 48 h each.

Facile preparation of biodegradable glycol chitosan hydrogels using divinyladipate as a crosslinker

Biodegradable, pH-sensitive, glycol chitosan (GC) hydrogels were prepared using divinyl adipate (DVA) as a crosslinker and acetic acid as a catalyst. DVA has highly reactive double vinyl ester groups and GC contains a high density of hydroxyl groups, with two in every glucosamine unit. The transesterification reaction between vinyl esters and hydroxyl groups produced crosslinked GC hydrogels. The initial crosslinking reaction was monitored by measur- ing the viscosity of the reaction mixture. When DVA was added to the GC solution and heated to 50 C, the viscosity of the GC solution gradually increased, implying a crosslinking reaction and hydrogel formation. A new peak from the ester group was observed in the FTIR spectra of the GC hydrogels, confirming the crosslinking reaction. The syn- thesized GC hydrogel showed pH-dependent water absorbency, mainly due to the presence of amine groups (-NH ) at the C-2 position of the glucosamine unit of GC. The water absorbency greatly increased at acidic pH and slightly decreased at alkaline pH. The GC hydrogel gradually degraded in 37 C water due to hydrolysis of the ester bonds, which were intermolecular crosslinking sites. A red dye, 5-carboxyltetramethyl-rhodamine (CTMR), was entrapped in the GC hydrogels as a model compound. CTMR was released from GC hydrogels in two steps: an initial burst release mainly due to desorption and diffusion, and a second sustained release possibly due to gradual degradation.

Distinction Between Esterases and Lipases: Comparative Biochemical Properties of Sequence-Related Carboxylesterases

Carboxylesterases (Carboxyl ester hydrolase) include two groups of enzymes, namely non-specific esterases (EC 3.1.1.1) and lipases (EC 3.1.1.3) which have been early differentiated on the basis of their substrate specificity. Esterases hydrolyse solutions of water-soluble short acyl chain esters and are inactive against water-insoluble long chain triacylglycerols which, in turn, are specifically hydrolyzed by lipases. Based on the comparison of the primary structures, three families of sequence-related carboxylesterases, namely the lipoprotein lipase family (L-family), the hormonesensitive lipase family (H-family) and the cholinesterase family (C-family) have been identified. Using solutions and emulsions of vinyl, glyceryl and p-nitrophenyl esters, we have reinvestigated the kinetic properties of some esterases and lipases of the H- and C-families. Results indicate that esterases and lipases, which are both active on soluble esters, can be differentiated by their value of Km. Moreover, esterase, unlike lipases, are inactive against water-insoluble esters as vinyl laurate and trioctanoylglycerol. From the the comparison of structural features of sequence-related esterases and lipases, it appears that lipases, unlike esterases, display a significant difference in the distribution of hydrophobic amino acid residues at vicinity of their active site. This observation supports the hypothesis of the existence in lipases of a particular surface domain that specifically interacts with lipid-water interfaces and contributes to the transfer a single substrate molecule from the organized lipid-water interface (supersubstrate) to the catalytic site of the enzyme.

Novel, Highly Efficient and Selective Ruthenium Catalysts for the Synthesis of Vinyl Esters from Carboxylic Acids and Alkynes

AbstractAn efficient and highly selective synthesis of vinyl esters was developed that employed carboxylic acids and terminal alkynes as reagents, and novel tethered (η1:η6‐phosphanoarene)ruthenium complexes as catalyst precursors. With these catalyst systems, the reactions were somewhat slower than when using the best catalysts reported to date, but the selectivities were excellent with up to 98 % of the Markovnikov isomer. In addition, with a turnover number (TON) of 5000, these catalysts greatly outperformed their competitors. Minute amounts of water had a beneficial impact on the reaction rates, while maintaining the same selectivities. Furthermore, microwave heating at 160 °C also considerably accelerated the reactions, albeit to the detriment of the selectivity. Finally, it should also be noted that formation of dimerization products of 1‐alkynes was completely suppressed by using these tethered (η1:η6‐phosphanoarene)ruthenium catalytic systems.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Ruthenium–arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands: Evaluation of their catalytic activity in the synthesis of enol esters

The catalytic activity of four ruthenium imidazol(in)ium-2-dithiocarboxylates was evaluated for the synthesis of vinyl esters through addition of 4-acetoxybenzoic acid to 1-hexyne, and compared to those of the parent ruthenium– N-heterocyclic carbene complexes and [RuCl 2( p-cymene)(PPh 3)] (a standard catalyst). It turned out that ruthenium imidazol(in)ium-2-dithiocarboxylates were poorly active and selective. Quantitative yields, indeed, were obtained only after extended reaction times. However, the catalytic activity could be improved significantly under microwave heating or conventional heating in a sealed tube at 160 °C, driving the reaction to completion in less than 4 h of reaction.

A highly regioselective route to arbutin esters by immobilized lipase from Penicillium expansum

Immobilized lipase from Penicillium expansum, a novel and inexpensive enzyme preparation that we immobilized in our laboratory, was an excellent catalyst for highly regioselective acylation of arbutin with fatty acid vinyl esters. For the enzymatic butanoylation of arbutin, under the optimal conditions, initial reaction rate was 75.1 mM/h, and substrate conversion and regioselectivity were greater than 99%. In addition, a variety of 6′-esters of arbutin were prepared with high conversion (>99%) and excellent regioselectivity (>99%). It was found that the enzymatic reaction rate varied widely with different acyl donors, presumably owing to their different interactions with the active site of the lipase. The immobilized lipase from P. expansum displayed highest catalytic activity with medium-length straight-chain acyl donors. Acyl donors bearing a substituent or a conjugate double bond gave reduced reaction rates.

A Versatile Catalyst System for Suzuki−Miyaura Cross-Coupling Reactions of C(sp2)-Tosylates and Mesylates

A catalyst system for the Suzuki-Miyaura cross-coupling reactions of aryl and vinyl tosylates and mesylates has been developed. This catalyst displays excellent functional group tolerance and allows the coupling of heteroarylboronic acids with aryl tosylates and mesylates to be performed in high yields. Moreover, reactions employing alkylboronic acids, as well as heteroaryl, vinyl, and allylic pinacol boronate esters, were conducted with high efficiencies.

A molecular modelling approach to rationalize the stereochemical outcome of the Burkholderia cepacia lipase-catalyzed transesterification of aromatic primary alcohols with vinyl esters with different chain lengths in chloroform

The Burkholderia cepacia lipase-catalyzed transesterification of 2-methyl-3-phenyl-1-propanol with vinyl esters proceeds with high enantioselectivity independently of the acyl chain length and the low enantioselectivity of the same reaction with 2-phenyl-1-propanol is not affected by chain length of the vinyl esters. A molecular modelling approach has been developed in order to rationalize the enzymatic results.

Efficiently enhancing regioselective acylation of 5‐azacytidine catalysed by Candida antarctica lipase B with co‐solvent mixtures as the reaction media

A comparative study of regioselective acylation of 5-azacytidine catalysed by CAL-B (Candida antarctica lipase B) in co-solvent mixtures and in pure organic solvents was performed, to our knowledge for the first time, and it was shown that a remarkable enhancement in the initial rate and substrate conversion in the reaction could be achieved with co-solvents as the reaction medium instead of pure organic solvents. For the CAL-B-catalysed regioselective synthesis of 5'-O-butyryl-5-azacytidine in co-solvent mixtures, the optimal conditions were as follows: optimal co-solvent mixture, hexane/pyridine (40/60, v/v); initial aw (water activity), 0.07; enzyme dosage, 50 units/ml; vinyl butyrate/5-azacytidine molar ratio, 15:1; temperature, 60 °C. Under the optimal conditions, v0 (the initial reaction rate), C (the substrate conversion) and the regioselectivity of the reaction were 0.75 mM/min, 99.0% and above 99% respectively. Similar phenomena were observed in the CAL-B-catalysed regioselective acylation of 5-azacytidine with an extensive range of fatty acid vinyl esters (from C2 to C18). Compared with pure pyridine, the reactions were greatly accelerated in a hexane/pyridine (40/60, v/v) co-solvent mixture and 5-azacytidine could be biotransformed into its derivative 5'-O-acyl-5-azacytidine at a much higher conversion rate (91.4-99.0% as against 40.2-43.5%). Meanwhile, adoption of a co-solvent mixture as the reaction medium could also greatly lower the enzyme dosage and the molar ratio of acyl donor to 5-azacytidine.

Identification and biochemical characterization of a GDSL-motif carboxylester hydrolase from Carica papaya latex

An esterase (CpEst) showing high specific activities on tributyrin and short chain vinyl esters was obtained from Carica papaya latex after an extraction step with zwitterionic detergent and sonication, followed by gel filtration chromatography. Although the protein could not be purified to complete homogeneity due to its presence in high molecular mass aggregates, a major protein band with an apparent molecular mass of 41 kDa was obtained by SDS-PAGE. This material was digested with trypsin and the amino acid sequences of the tryptic peptides were determined by LC/ESI/MS/MS. These sequences were used to identify a partial cDNA (679 bp) from expressed sequence tags (ESTs) of C. papaya. Based upon EST sequences, a full-length gene was identified in the genome of C. papaya, with an open reading frame of 1029 bp encoding a protein of 343 amino acid residues, with a theoretical molecular mass of 38 kDa. From sequence analysis, CpEst was identified as a GDSL-motif carboxylester hydrolase belonging to the SGNH protein family and four potential N-glycosylation sites were identified. The putative catalytic triad was localised (Ser 35-Asp 307-His 310) with the nucleophile serine being part of the GDSL-motif. A 3D-model of CpEst was built from known X-ray structures and sequence alignments and the catalytic triad was found to be exposed at the surface of the molecule, thus confirming the results of CpEst inhibition by tetrahydrolipstatin suggesting a direct accessibility of the inhibitor to the active site.

Substrate specificity of lipase from Burkholderia cepacia in the synthesis of 3′-arylaliphatic acid esters of floxuridine

Among the five vinyl esters bearing phenyl ring in acyl moiety, the lipase from Burkholderia cepacia was most specific toward vinyl 4-phenylbutyrate. Additionally, 3′-regioselectivity of the enzyme was enhanced with the increment of acyl chain length. The lipophilic 3′-arylaliphatic acid esters of floxuridine, its potential prodrugs, were synthesized with high conversions (>98%) and good to excellent regioselectivities (85–99%) via the enzymatic approach.

Carica papaya lipase-catalyzed transesterification resolution of secondary alcohols in organic solvents

Aside from the capability in lipids bioconversion and kinetic resolution of chiral acids, Carica papaya lipase (CPL) as a naturally immobilized enzyme is explored as a potential biocatalyst for the transesterification resolution of chiral secondary alcohols with vinyl esters as the acyl donor in anhydrous solvents. A substrate-type model was proposed for interpreting the enzyme stereochemical preference, showing low enantioselectivity for all tested secondary alcohols except for ( R, S)-methyl 3-phenyllactate ( 2). The kinetic analysis further revealed that the high enantioselectivity was mainly due to the prompt proton transfer from fast-reacting ( S)- 2 to the imidazole moiety of catalytic histidine in the deacylation step, as well as the low enzyme specific activity for ( R)- 1 or ( S)- 1 was owing to the difficult substrate affinity to the active site. Effects of changing the solvent, vinyl ester, and enzyme pretreatments on the lipase performance were also reported.

Lipase-mediated enantioselective acylation of alcohols with functionalized vinyl esters: acyl donor tolerance and applications

Enzymatic acylation is commonly used for the kinetic resolution of alcohols and amines. The simple acyl group introduced during the enzymatic reaction is usually removed or replaced by another group. Retention of more complex acyl moieties as part of the target structures would be a more efficient strategy. We have studied the enantioselective acylation of a model alcohol substrate, 1-phenylethanol, with vinyl esters bearing various functionality on the acyl moieties in the presence of three lipases ( Candida antarctica, Candida rugosa and Burkholderia cepacia) frequently used in organic synthesis. C. antarctica lipase is the most versatile lipase for this type of biotransformations. We applied this strategy to the synthesis of a protein kinase C ligand and a natural product, phoracantholide.

Controllable enzymatic Markovnikov addition and acylation of thiols to vinyl esters

The chemical selectivity between Markovnikov addition and acylation in the reaction of thiols and vinyl esters were developed. The addition reaction was efficiently catalyzed by CAL-B at 50 °C in isopropyl ether, affording the Markovnikov adducts with good yields. Acylation was carried out under the catalysis of d-amino acylase in DMF at 50 °C. A series of thioethers and thioesters were synthesized via the controllable enzymatic methods.

A simple procedure for the synthesis of potential 6-azauridine prodrugs by Thermomyces lanuginosus lipase

Highly regioselective acylation of 6-azauridine with fatty acid vinyl esters catalyzed by the lipase from Thermomyces lanuginosa for the preparation of its 5′- O-acyl derivatives has been successfully performed for the first time. The effects of some crucial factors on the enzymatic palmitoylation of 6-azauridine were further examined. The optimum reaction medium, molar ratio of 6-azauridine to vinyl palmitate, reaction temperature and enzyme dosage were found to be anhydrous acetone, 1:7, 40 °C and 450 U/ml, under which the reaction rate, the substrate conversion and the regioselectivity were 13.3 mM/h, 98.4% and 99.0%, respectively. Moreover, the acyl recognition of the enzyme in the regioselective acylation of 6-azauridine was investigated. The results showed that although 5′- O-acyl derivatives of 6-azauridine were exclusively obtained with all the tested acyl donors, the enzymatic activity varied widely with different acyl donors owing to the specific structures of the lipase's active site and the acyl donors.

Unusual Mechanistic Course of Some NHC-Mediated Transesterifications

During experiments on the transesterification of vinyl benzoate with ethanol mediated by IPr and IMes, unexpected species were observed and characterized that call into question the accepted mechanism of the NHC-mediated transesterification of vinyl esters.

On the nature of ionic liquids and their effects on lipases that catalyze ester synthesis

Free and immobilized lipases from Candida antarctica (CALA and CALB), Thermomyces lanuginosus (TLL) and Rhizomucor miehei (RML) were used as catalysts in the synthesis of butyl propionate by transesterification in reaction media consisting in nine different ionic liquids. Enzyme activities were clearly dependent on the nature of the ions, the results being improving as the alkyl chain length of the imidazolium cation increased, and as a function of the type of anion ([PF6], [BF4] or [ethylsulphate]). The best synthetic activity (655.5U/mg protein at 40°C) was obtained when free CALB were assayed in the water-miscible IL cocosalkyl pentaethoxy methyl ammonium methosulfate ([CPMA][MS]), and was clearly related with the water content of the medium. The synthetic activity of free CALB in [CPMA][MS] was enhanced with the increase in temperature, while practically no effect was obtained for TLL. The ability of free CALB to synthesize aliphatic esters of different alkyl chain lengths, using different alkyl vinyl esters and 1-alkanols as substrates, was also studied in [CPMA][MS], the best results (4500U/mg protein) being obtained for the synthesis of hexyl butyrate.